Human immunodeficiency virus type 1 (HIV-1) encodes a 160 kDa envelope glycoprotein (gp160) precursor, which is proteolytically cleaved into the exterior (gp120) and transmembrane (gp41) glycoproteins.
In the glycoprotein mature envelope, the gp120 glycoprotein remains associated with the gp41 ectodomain through a noncovalent interaction. The native HIV-1 envelope glycoproteins exist as trimers that consist of three gp120 and three gp41 subunits and is anchored in the viral or infected cell membrane by the gp41 transmembrane region.
It has been shown that the binding of gp120 to the CD4 receptor induces conformational changes that promote subsequent interaction with one of a number of chemokine receptors (CXCR4, CCR5 . . . ). These binding events trigger conformational changes in gp41. In particular, studies by X-ray crystallography and nuclear magnetic resonance indicate that the viral envelope glycoprotein gp41 exists in at least three conformations, a native conformation (spike), a prefusogenic metastable conformation which is converted to a thermostable fusogenic “three hairpin” conformation following a triggering event, such as binding of HIV virus particle to the membrane of target cells.
So, the binding of gp120 to cellular coreceptors induces the gp41 conversion of a prefusogic form to a fusogenic form.
The linear organization of the gp41 includes a fusion peptide, an ectodomain (a N-terminal coiled-coil, a disulfide-bonded loop region, and a C-terminal α-helical segment) and a transmembrane domain.
In the fusogenic six-helix bundle, three N-terminal helices form a trimeric coiled-coil, and three C-terminal helices pack in the reverse direction into three hydrophobic grooves on the surface of the coiled-coil. This helical-hairpin structure corresponds to the fusion-active conformation of gp41. Because the membrane anchor and the fusion peptide of the gp41 ectodomain are embedded in the viral and target cell membranes, respectively, the formation of the fusogenic hairpin structure results in the colocalization of the two membranes and thus overcomes the energy barrier for membrane fusion.
The envelope glycoproteins represent the only realistic viral target for vaccine-induced neutralizing antibody responses because they promote viral membrane fusion through receptor-mediated conformational change and they are expressed on the surface of both virions and infected cells. Monomeric HIV-1 gp120 and derivatives were initially considered to be principal vaccine candidates. However, HIV-1 gp120 is highly variable and has repeatedly proven to be an immunogen ineffective at eliciting neutralizing antibodies against clinical HIV-1 isolates. Few of the antibodies raised by gp120 monomers effectively bind assembled HIV-1 envelope glycoprotein trimers.
In contrast, gp41 is an extremely immunogenic glycoprotein, inducing antibodies in essentially all HIV-infected individuals.